DESCRIPTION (Investigator's Abstract): The long term goal of this research is the determination of cellular mechanisms of opioid actions on nociceptive (pain) neurons. Because opioids are among the most effective agents for relieving pain, they are thought of as inhibitory agents. Yet, there are many examples in which opioids exert direct excitatory actions on nociceptive neurons. One of the clinically important features of opioid antinociception is that opioids are very effective in relieving inflammatory pain, but are ineffective for neuropathic pain. The focus of this grant is to determine the role(s) of the opioid-induced excitatory responses in inflammatory and neuropathic pain states. The applicants hypothesize that opioid actions are a balance between excitatory and inhibitory effects and a major difference between the actions of opioids on inflammatory as opposed to neuropathic pain is that the balance is tipped towards the excitatory side in the neuropathic state. To test this hypothesis, they will (1) compare the mechanisms by which opioids affect excitatory and inhibitory amino acid responses in dorsal horn neurons isolated from normal, inflamed (i.e., arthritic) and neuropathic animals, and (2) compare the effects of opioids on Ca2+ mobilization in dorsal horn neurons and in primary afferent terminals of these animals. The experiments will be performed on single dorsal horn neurons and spinal cord slices. The membrane currents will be monitored with perforated patch electrodes; the intracellular Ca2+ concentrations will be measured using fluorescence Ca2+ indications. These experiments will provide information about the mechanisms underlying excitatory actions of opioids in the normal, inflammatory and neuropathic states. The knowledge will aid us in developing new drugs and better strategies for the treatment of pain. In addition, the study will facilitate a better understanding of mechanisms underlying the plasticity in nociceptive systems in general.